Cancer is a disease whose causes are to be seen, inter alia, in disturbed signal transduction. In particular, deregulated signal transduction via tyrosine kinases plays a central role in the growth and spread of cancer (Blume-Jensen, P. and T. Hunter, Nature 411: 355-365, 2001; Hanahan D. and R. A. Weinberg, Cell 100:57-70, 2000). Tyrosine kinases and in particular receptor tyrosine kinases and the growth factors binding to them may thus be involved in deregulated apoptosis, tissue invasion, metastasis and generally in signal transduction mechanisms which lead to cancer.
As already mentioned, one of the principal mechanisms by which cellular regulation is effected is the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. Protein phosphorylation represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in a cellular response. These signal transduction cascades are highly regulated and often overlap, as is evident from the existence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly at serine, threonine or tyrosine residues, and protein kinases have therefore been classified by their specificity of phosphorylation site, i.e. serine/threonine kinases and tyrosine kinases. Since phosphorylation is a very widespread process within cells and since cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a large number of conditions and/or diseases are attributable to either aberrant activation or functional mutations in the molecular components of kinase cascades. Consequently, considerable attention has been devoted to the characterization of these proteins and compounds that are able to modulate their activity (see review article: Weinstein-Oppenheimer et al., Pharma. &. Therap. 88:229-279, 2000). Various possibilities for the inhibition, regulation and modulation of kinases encompass, for example, the provision of antibodies, antisense ribozymes and inhibitors. In oncology research, tyrosine kinases, in particular, are highly promising targets. Thus, numerous synthetic small molecules are undergoing clinical development as tyrosine kinase inhibitors for the treatment of cancer, for example Iressa® or Gleevec®. However, numerous problems, such as side effects, dosage, resistance of the tumour, tumour specificity and patient selection, still have to be solved here.
Tyrosine kinases are a class of enzymes which catalyse the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. It is thought that tyrosine kinases, through substrate phosphorylation, play a crucial role in signal transduction for a number of cellular functions. Although the precise mechanisms of signal transduction are still unclear, tyrosine kinases have been shown to be important factors in cell proliferation, carcinogenesis and cell differentiation.
Tyrosine kinases can be categorised as receptor tyrosine kinases or non-receptor tyrosine kinases. Receptor tyrosine kinases have an extracellular portion, a transmembrane portion and an intracellular portion, while non-receptor tyrosine kinases are exclusively intracellular.
Receptor tyrosine kinases consist of a multiplicity of transmembrane receptors with different biological activity. Thus, about 20 different sub-families of receptor tyrosine kinases have been identified. One tyrosine kinase subfamily, known as the EGFR or HER subfamily, consists of EGFR, HER2, HER3 and HER4. Ligands from this subfamily of receptors include epithelial growth factor (EGF), tissue growth factor (TGF-α), amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR and IR-R. The PDGF subfamily includes the PDGF-α and -β receptor, CSFIR, c-kit and FLK-II. In addition, there is the FLK family, which consists of the kinase insert domain receptor (KDR) or VEGFR-2, foetal liver kinase-1 (FLK-1), foetal liver kinase-4 (FLK-4) and fms tyrosine kinase-1 (flt-1) or VEGFR-1. The PDGF and FLK family are usually combined in the group of the split kinase domain receptor tyrosine kinases (Laird, A. D. and J. M. Cherrington, Expert. Opin. Investig. Drugs 12(1): 51-64, 2003) due to the similarities between the two groups. For a detailed discussion of receptor tyrosine kinases, see the paper by Plowman et al., DN & P 7(6):334-339 (1994).
Non-receptor tyrosine kinases likewise consist of a multiplicity of subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into different subgroups. For example, the Src subfamily is one of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of non-receptor tyrosine kinases, see the paper by Bolen, Oncogene, 8:2025-2031 (1993).
Both receptor tyrosine kinases and non-receptor tyrosine kinases are involved in cellular signal transfer pathways leading to conditions such as cancer, psoriasis and hyperimmune responses.
The present invention relates to compounds of the formula I, preferably as regulators, modulators or inhibitors of receptor tyrosine kinases of the insulin subfamily, which includes the insulin receptor IR, the “insulin like growth factor-1 receptor” IGF-1R and the “insulin related receptor” IRR. The compounds according to the invention are particularly effective in the inhibition of the receptor tyrosine kinase IGF-1R.
As previously mentioned, the insulin-like growth factor-1 receptor (IGF-1R) belongs to the family of transmembrane tyrosine kinase receptors, such as platelet-derived growth factor receptor, the epidermal growth factor receptor, and the insulin receptor. There are two known ligands for the IGF-1R receptor. They are IGF-1 and IGF-2. As used herein, the term “IGF” refers to both IGF-1 and IGF-2. A review of the insulin-like growth factor family of ligands, receptors and binding proteins is given in Krywicki and Yee, Breast Cancer Research and Treatment, 22:7-19, 1992.
IGF/IGF-1R-induced diseases are characterised by an anomalous activity or hyperactivity of IGF/IGF-1R. Anomalous IGF activity refers to either: (1) IGF or IGF-1R expression in cells which do not normally express IGF or IGF-1R; (2) increased IGF or IGF-1R expression leading to undesired cell proliferation, such as cancer; (3) increased IGF or IGF-1R activity leading to undesired cell proliferation, such as cancer, and/or hyperactivity of IGF or IGF-1R. Hyperactivity of IGF or IGF-1R refers to either an amplification of the gene encoding IGF-1, IGF-2, IGF1R or the production of a level of IGF activity which can be correlated with a cell proliferative disease (i.e. as the level of IGF increases, the severity of one or more symptoms of the cell proliferative disease increases) the bioavailability of IGF-1 and IGF-2 can also be affected by the presence or absence of a set of IGF binding proteins (IGF-BPs) of which six are known, Hyperactivity of IGF/IGF-1R can also result from downregulation of IGF-2 which contains an IGF-2 binding domain, but no intracellular kinase domain. Examples of IGF/IGF-1R-induced diseases include the various IGF/IGF-1R-related human malignancies reviewed in Cullen et al., Cancer Investigation, 9(4):443-454, 1991. For the clinical importance and role of IGF/IGF-1Rs in regulating osteoblast function, see Schmid, Journal of Internal Medicine, 234:535-542, 1993.
The activites of IGF-1R thus include: (1) phosphorylation of IGF-1R protein; (2) phosphorylation of an IGF-1R protein substrate; (3) interaction with an IGF adapter protein; (4) IGF-1R protein surface expression. Further IGF-1R protein activities can be identified using standard techniques. IGF-1R activity can be assayed by measuring one or more of the following activities: (1) phosphorylation of IGF-1R; (2) phosphorylation of an IGF-1R substrate; (3) activation of an IGF1R adapter molecule and (4) activation of downstream signalling molecules and/or (5) increased cell division. These activities can be measured using techniques described below and known in the prior art.
IGF-1R has been regarded as essential for the establishment and maintenance of the transformed phenotype in vitro and in vivo in a number of cell types (R. Baserga, Cancer Research 55:249-252, 1995). Herbimycin A has been said to inhibit IGF-1R protein tyrosine kinase and cell proliferation in human breast cancer cells (Sepp-Lorenzino et al., J. Cell Biochem. Suppl. 18b:246, 1994). Experiments studying the role of IGF-1R in transformation that have used antisense strategies, dominant negative mutations, and antibodies to IGF-1R have led to the hypothesis that IGR-1R may be a preferred target for therapeutic interventions.
In addition to its role in nutritional support and in type-II diabetes, IGF-1R has also been associated with several types of cancer. For example, IGF-1 has been implicated as an autocrine growth stimulator for several tumour types, e.g. human breast cancer carcinoma cells (Arteago et al., J. Clin. Invest., 84:1418-1423, 1989) and small lung tumour cells (Macauley et al., Cancer Res., 50:2511-2517, 1989). In addition, IGF-1, while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg-Nordqvist et al., Cancer Res., 53:2475-2478 (1993).
An example of the potential involvement of IGF-2 in colorectal cancer may be found in the upregulation of IGF-2 mRNA in colon tumours relative to normal colon tissues (Zhang et al., Science:276; 1268-1272, 1997) IGF-2 may also play a role in hypoxia-induced neovascularisation of tumours. (Mines et al., Int. J. Mol. Med. 5:253-259, 2000) IGF-2 may also play a role in tumourigenesis through activation of an insulin receptor isoform A. IGF-2 activation of insulin receptor isoform A activates cell survival signalling pathways, but its relative contribution to tumour cell growth and survival is unknown at this time. The kinase domain of insulin receptor isoform A is identical to that of the standard insulin receptor (Scalia et al., J. Cell Biochem. 82:610-618, 2001).
The importance of IGF-1R and its ligands in cell types in culture (fibro-blasts, epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)) is illustrated by the ability of IGF-1 to stimulate cell growth and proliferation (Goldring and Goldring, Eukaryotic Gene Expression, 1:301-326, 1991). In a series of recent publications, Baserga et al. suggest that IGF-1R plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions in a broad range of human malignant diseases (Baserga, Cancer Res., 55:249-252, 1995; Baserga, Cell, 79:927-930, 1994; Coppola et al., Mol. Cell. Biol., 14:4588-4595, 1994; Baserga, Trends in Biotechnology, 14:150-152, 1996; H. M. Khandwala et al., Endocrine Reviews, 21:215-244, 2000).
The most important types of cancer that can be treated using a compound according to the invention include breast cancer, prostate cancer, colorectal cancer, small-cell lung cancer, non-small-cell lung cancer, multiple myeloma and renal cell carcinoma and endometrial carcinoma.
IGF-1 has also been associated with retinal neovascularisation. Proliferative diabetic retinopathy has been observed in some patients having high levels of IGF-1. (L. E. Smith et al., Nature Medicine, 5:1390-1395, 1999)
However, the compounds according to the invention may also be suitable as anti-ageing agents. It has been observed that there is a link between IGF signalling and ageing. Experiments have shown that calorie-restricted mammals have low levels of insulin and IGF-1 and have a longer life span. Similar observations have also been made in the case of insects (see C. Kenyon, Cell, 105:165-168, 2001; E. Strauss, Science, 292:41-43, 2001; K. D. Kimura et al., Science, 277:942-946, 1997; M. Tatar et al., Science, 292:107-110, 2001).
The present invention thus also relates to the use of the compounds of the formula I for the prevention and/or treatment of diseases in connection with unregulated or disturbed receptor activity. In particular, the compounds according to the invention can therefore be employed in the treatment of certain forms of cancer, such as, for example, breast cancer, prostate cancer, intestinal cancer, small-cell and non-small-cell lung cancer, multiple myeloma, renal-cell carcinoma or corpus carcinoma.
Also conceivable is the use of the compounds according to the invention for the treatment of diabetic retinopathy or for delaying the ageing process. In particular, they are suitable for use in diagnostic methods for diseases in connection with unregulated or disturbed IGF-1R activity.
In addition, the compounds according to the invention can be used to achieve additive or synergistic effects in certain existing cancer chemotherapies and radiotherapies and/or for restoring the efficacy of certain existing cancer chemotherapies and radiotherapies.
A number of aza-heterocyclic compounds have hitherto been described as kinase inhibitors, for example in WO 03/018021, WO 03/018021 or WO 04/056807.
The invention was therefore based on the object of finding novel compounds having advantageous therapeutic properties which can be used for the preparation of medicaments.
Thus, the identification and provision of chemical compounds which specifically inhibit, regulate and/or modulate tyrosine kinase signal transduction is desirable and therefore an aim of the present invention.